International patent application WO 99/59957 and J. Med. Chem. 2003, 46, 303-309 describe the synthesis of some new compounds having inhibiting activity against carnitine palmitoyl transferase (CPT).
Among the compounds synthesized and tested one of the most interesting is R-4-trimethylammonium-3-(tetradecylcarbamoyl)-amino butyrate (also named ST 1326 or teglicar [INN]), whose synthesis is reported in Example 15 of WO 99/59957, and which corresponds to compound 17 of J. Med. Chem. 2003, 46, 303-309.
This compound was described as an agent able to selectively inhibit in vitro L-CPT I (liver CPT isoform I) with respect to M-CPT I (muscle CPT isoform I) and to depress ketogenesis in vivo (fasted rats). It also showed a good reduction of serum glucose levels in a diabetic mouse model, without any significant change in heart weight and triglycerides content. Owing to its encouraging activity and pharmacological profile, this compound was selected as a candidate for clinical development as an antiketotic and antidiabetic drug.
WO 2005/077354 discloses the use of the same compound for the preparation of an anti-tumour medicament.
However neither of these references indicate whether this compound is obtained in an amorphous or in a crystalline state.
Repetition of the preparation methods reported in these two references (WO 99/59957 and J. Med. Chem. 2003, 46, 303-309) has now allowed to establish that this compound was obtained as a mixture of a crystalline and an amorphous form.
X ray powder diffraction is the most widely used technique in the identification and characterisation of crystalline solids, each of which produces a distinctive diffraction pattern. Both the positions and the relative intensity of the lines are indicative of a particular phase and material, providing a “fingerprint” for comparison.
In contrast to a crystalline pattern consisting of a series of sharp peaks, amorphous materials (liquids, glasses etc.) produce a broad background signal. Powder X ray diffraction can be used to determine the crystallinity of the different preparations of the same product.
Many drugs, old and new, were discovered and rushed into market as their ‘suitable’ crystalline forms and had never been screened thoroughly for their potential polymorphic forms. With the recent technological advancement of solid state chemistry, it is possible that new polymorphic forms can be discovered, which have never been seen before.
The new polymorphic forms are often able to deliver therapeutic advantages and represent one of the new challenges of the pharmaceutical industry. As a matter of fact polymorphism, the ability of a molecule to crystallize into more than one crystal arrangement, can have a profound effect on the shelf life, solubility, formulation properties, and processing properties of a drug.
More importantly, the action of a drug can be affected by the polymorphism of the drug molecules. Different polymorphs can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even be toxic. The occurrence of an unknown polymorphic form during manufacture can have an enormous impact on a drug company.
Therefore it is vital that researchers involved in the formulation of crystalline products be able to select the polymorph with the correct properties and anticipate problems such as the unwanted crystallization of other polymorphs.
Surprisingly, a very large number of pharmaceuticals exhibit the phenomenon of polymorphism. 70% of barbiturates, 60% of sulfonamides and 23% of steroids exist in different polymorphic forms.
Conducting a crystallization study on teglicar led to the claimed invention.